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Drug Metabolism and Pharmacokinetics Core. Goal: To provide comprehensive pharmacology support for preclinical and clinical research. Services:. Pharmacokinetic studies: Quantify drug levels in serum/plasma, tissue or cells

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Drug Metabolism and Pharmacokinetics Core

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Drug metabolism and pharmacokinetics core l.jpg

Drug Metabolism and Pharmacokinetics Core

Goal: To provide comprehensive pharmacology support for preclinical and clinical research


Services l.jpg

Services:

  • Pharmacokinetic studies: Quantify drug levels in serum/plasma, tissue or cells

  • Evaluation of Organ Toxicity: Blood chemistry analysis for liver, kidney and bone marrow toxicity

  • Hematology: Measure complete blood counts

  • Measure GSH/GSSG

  • Redox analysis: Detection of protein thiol status in cells, tissue, serum and plasma.

  • Education and training


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NOV-002, a myeloproliferative agent

Phase II: Neo-adjuvant breast cancer trial at MUSC


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Pharmacokinetic Analysis


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A.

ug/mL GSSG

B.

ug/mL GSH


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Estimated pharmacokinetic parameters for NOV-002 (GSSG) and its primary metabolite (GSH)

PK ParameterGSH GSSG

Co (ug/mL) 4.10 0.65

Cmax (ug/mL) 18.30 2.16

Tmax (hr) 0.16 0.15

Volume of distribution, V/F (L/kg) 42.61

K01 (absorption rate constant), hr-1 6.42

K10 (elimination rate constant), hr-15.81 6.40

AUC 0-30min (ug.h/mL)6.37 1.18

Clearance, CL/F (L/hr/kg) 273.15


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Evaluation of Organ Toxicity


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  • Table 2. Mortality and Nephrotoxicity of Cisplatin in Mice

  • Elevated Abnormal

  • Mortality Creatinine Renal Histology

  • Saline0/6*0/60/6

  • NOV-0020/60/60/6

  • Cisplatin1/8§ 6/7§7/7§

  • Cisplatin + NOV-0020/93/93/9

  • Data are the number of mice who died, had elevated plasma creatinine (>0.2 mg/dL) or abnormal renal histology over the number of mice treated.

  • § Statistically significant differences between treatment groups were detected with a Fisher Exact Test, P<0.01.


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Saline NOV-002

Cisplatin Cisplatin + NOV-002


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Hematology:


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Normal 6 x 109

Female +/+

x 109 cells/mL

Female Male

Cisplatin + +

NOV-002 - +

Cisplatin Induced Bone Marrow ToxicityWhite Blood Cells

  • HM2 Hematology System (Abaxis)


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Measure GSH/GSSGRedox Potential

Eh (mV)


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-S-TGTM

+ TGTM

-SH

-S-SG

+

NOV-002

Redox analysis:

*

*

% Free Sulfhydryls

*

*


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NOV-002 (25 mg/kg, iv)

0 ¼ ½ 1 4 24 h

Kda

150

100

75

50

37

A

B

C

D

WB: PSSG

WB: actin

Identification of Plasma Markers following NOV-002 treatment


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Cost Recovery System:

  • Assay Development$1,500 + Column

  • PK Modeling$50/ hr

  • Plasma / Serum Assay$50 / sample

  • Organ toxicity analysis$35 / sample

  • Hematology (CBC)$20 / sample

  • GSH/GSSG levels$25 / sample

  • Protein Thiol Analysis$35 / sample

  • Breeze HPLC

    • User Operated Training$ 50 / hour

    • User Operation fee$ 25 / hour

    • Over-night / weekend fee$18 / hour


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Drug Metabolism and Pharmacokinetics Core

Drug Discovery Building 420

843-876-2391

Danyelle Townsend, Ph.D., DirectorYefim Manevich, Ph.D.,

Drug Discovery Building [email protected]

843-876-2391

[email protected]

Joachim Uys, Ph.D.

PK project manager

[email protected]


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